Purpose: Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase after exposure to pro-inflammatory stimuli and, therefore, represents a novel target for therapeutic treatment of acute and chronic inflammatory disorders. However, in this study, we aimed to identify novel inhibitors of mPGES-1 with new scaffolds through structure-based virtual screening. Methods: We carried out combined structure-based virtual screening and experimental studies in order to identity novel inhibitors of mPGES-1. Our virtual screening was performed on compounds in the SPECS and NCI libraries, containing a total of ~500,000 available compounds. The virtual screening was followed by in vitro activity assays against mPGES-1. The identified active compounds were further tested against COX-2. Results: Based on the virtual screening, the top-50 compounds were ordered for in vitro activity assays against mPGES-1. According to the in vitro activity assays, 15 compounds can significantly inhibit mPGES-1 at 10 µM. Of the 15 compounds, 8 compounds have been determined for their IC50 values (200 nM to 8 µM). Further in vitro activity assays against COX-2 and other off targets indicate that most of these new inhibitors of mPGES-1 do not inhibit COX-2. Starting from these novel inhibitors with new scaffolds, more potent and selective inhibitors of mPGES-1 may be designed in the future. Conclusion: The structure-based virtual screening, followed by in vitro activity assays, has led to discovery of a set of novel inhibitors of mPGES-1 with new scaffolds.

Novel mPGES-1 inhibitors identified from structure-based virtual screening based on new acting mechanism

253rd National Meeting (2017)

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